title: Regenerative glutamate release by presynaptic NMDA receptors contributes to spreading depression.
abstract: Spreading depression (SD) is a slowly propagating neuronal depolarization that underlies certain neurologic conditions. The wave-like pattern of its propagation suggests that SD arises from an unusual form of neuronal communication. We used enzyme-based glutamate electrodes to show that during SD induced by transiently raising extracellular K(+) concentrations ([K(+)]o) in rat brain slices, there was a rapid increase in the extracellular glutamate concentration that required vesicular exocytosis but unlike fast synaptic transmission, still occurred when voltage-gated sodium and calcium channels (VGSC and VGCC) were blocked. Instead, presynaptic N-methyl-D-aspartate (NMDA) receptors (NMDARs) were activated during SD and could generate substantial glutamate release to support regenerative glutamate release and propagating waves when VGSCs and VGCCs were blocked. In calcium-free solutions, high [K(+)]o still triggered SD-like waves and glutamate efflux. Under such a condition, glutamate release was blocked by mitochondrial Na(+)/Ca(2+) exchanger inhibitors that likely blocked calcium release from mitochondria secondary to NMDA-induced Na(+) influx. Therefore presynaptic NMDA receptor activation is sufficient for triggering vesicular glutamate release during SD via both calcium entry and release from mitochondria by mitochondrial Na(+)/Ca(2+) exchanger. Our observations suggest that presynaptic NMDARs contribute to a cycle of glutamate-induced glutamate release that mediate high [K(+)]o-triggered SD.
authors.affiliation: 1] Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada [2] Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan [3] China Medical University, Taichung, Taiwan.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhou
authors.forename: Ravi L
authors.initials: RL
authors.lastname: Rungta
authors.forename: Aqsa
authors.initials: A
authors.lastname: Malik
authors.forename: Huili
authors.initials: H
authors.lastname: Han
authors.forename: Dong Chuan
authors.initials: DC
authors.lastname: Wu
authors.forename: Brian A
authors.initials: BA
authors.lastname: MacVicar
mesh_terms: D000818:Animals; D015374:Biosensing Techniques; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D013181:Cortical Spreading Depression / Q000502:physiology*; D004566:Electrodes; D004594:Electrophysiology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D011188:Potassium / Q000008:administration & dosage / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D017661:Receptors, Presynaptic; D019831:Sodium-Calcium Exchanger; D018698:Glutamic Acid; D011188:Potassium; D002118:Calcium